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56 Cards in this Set
- Front
- Back
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What are the old and new definitions of toxicology? |
Old: The scientific study of poisons and their actions and detection, and treatment of the condition produced by them. New: Study of the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem, including the prevention and amelioration of such adverse effects. |
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What is the definition of toxicant, toxin, teratogen, mutagen, carcinogen, and xenobiotic? |
Toxicant: Toxic at significantly high concentration Toxin: Toxicant produced by living organisms Teratogen: causes developmental malformations Mutagen: Changes genetic material Carcinogen: Causes cancer Xenobiotic: human-made substances |
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What is the Ebers papyrus? |
Earliest written toxicology document, information about hemlock, aconite, opium, cannabis, and metals |
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Who are the major figures in the development of toxicology?
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-Hippocrates: added poisons and clinical info -Theophrastus: Student of Aristotle, references poisonous plants in book De Historia Plantarum -Paracelsus: realized doses were important -Orfila: Forensic toxicology in autopsies |
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What were Paracelsus' principles? |
-Experimentation is essential in examination of responses to chemicals -One should distinguish therapeutic and toxic properties of chemicals as separate -Properties are sometimes distinguished by dose -One can ascertain a degree of specificity of chemicals and their therapeutic or toxic effects |
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What are the types of toxicology? |
-Mechanistic: focuses on how chemical, biochemical, and molecular mechanisms cause toxicants' effects -Descriptive: focuses on toxicity testing of chemicals, provides info for safety evaluation and regulatory requirements -Clinical toxicology: concerns diseases caused by toxicants -Forensic tox: focuses on medical and legal aspects, asks "why did they die?" -Reproductive tox: studies occurrence of adverse effects of toxicant exposure on reproductive systems -Developmental: studies life-long adverse effects of toxicants up to puberty -Occupational: focuses on hazards in workplace -Environmental: impacts on non-human organisms, ecotox- -Regulatory: focuses on risk decision-making based on data from mechanistic and descriptive, sets safety standards |
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What are the chemical characteristics of toxicants? |
Can be atoms (detected with atomic absorption spectroscopy), small molecules (HPLC and gas chromatography), or proteins (ELISA) Hydrophobicity varies |
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How is hydrophobicity of a toxicant determined and why is it important?? |
-Add the compound to equal parts water and octanol, shake it, and measure how much partitions into each phase
Kow = octanol-water partition coefficient log Kow: larger values mean chemical is more lipophilic Used to model where it is distributed, risk assessment |
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How is chromatography performed in forensic analysis? |
-Weigh part of a body -Extract the sample with non-polar solvents such as methanol or DCM -Extract is usually evaporated and extracted chemicals are re-suspended in solvent -Goes through injector and analyzed -Goes through column and molecules separated -Detector detects chemicals |
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How are molecules detected in HPLC? |
-Usually based upon absorbance of UV or visible light: anything with conjugated double or triple bonds absorbs UV light -Chromatogram appears -Compare chromatogram to that of standards and match for highest peak -Calculate area under curve and calculate how much of the chemical was in the sample |
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What is the process of a gas chromatograph? |
Carrier gas pumped through system (usually He) -sample injected into system via hot injector -sample volatized and carried to oven w/ column -Very volatile compounds pass through, most stick to beginning of the column -Oven starts cool, then ramps up in temp. Compounds released based upon volatility, then separated by hydrophobicity |
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What is electron ionization mass spectrometry? |
Used in GC detectors -stream of electrons hit molecules and ionizes and fragments them -ions go into quartz bars that generate a radiofrequency field which is swept up and down in frequency many times a second -Only ions of a specific mass make it through the quad at a specific frequency, hit a detector |
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How is atomic absorption spectrometry used? |
Specific atoms absorb specific wavelengths of light -if atom is in the sample, it will absor it and we measure the decrease of that wavelength |
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How is ELISA used? |
Proteins big so we use antibodies to bind the proteins we're interested in detecting -molecule they bind to is an antigen -the bit of the antigen that the antibody recognizes is called an epitope -Reapply another antibody specific for the protein making a sandwich, wash away unbound antibodies -Apply a third that binds to the second and has an enzyme attached to it -Substrate for enzyme added, reacts to produce a colour of the enzyme is there |
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What is the difference between a hazard and a risk?
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Hazard: condition having a negative effect on growth of a living organism at concentrations or levels of that condition likely to occur in the natural environment Risk: statistical probability that a hazard will occur |
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What factors affect the risk of a hazard?
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Being observable and controllable:
-Low risk if observable and controllable, high risk if not observable or controllable |
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What is risk assessment and risk management? |
Assessment: characterization of the probability of potentially adverse health effects from human exposures to environmental hazards Management: What we implement to reduce the incidence and/or negative consequences of the risk |
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What is epidemiology? |
The study of patterns, causes, and effects of health and disease conditions in defined populations |
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What is a bioassay in general? |
Quantitative estimation of intensity or concentration of a biologically active chemical, measured via biological response under standardized conditions -toxicity testing determines the range of dose over which toxic response occurs |
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What are the environmental uses of bioassays? |
-Determination of most sensitive species and/or life stages of organisms -Compare effects of different pollutants on a single organism -Compare effects of other environmental factors that modify effects of pollutants -Determination of the max level of a pollutant that may occur in the environment without causing biological change (Maximum Allowable Toxicant Concentration MATC) |
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What are the assumptions of bioassays? |
1. Effects produced in lab experiments are applicable to humans 2. High-dose exposure of experimental lab animals to toxic agents is a necessary and valid method of discovering possible hazards in humans 3. Positive bioassay showing toxicity is sufficient proof of a toxicity hazard in humans 4. Humans are at least as sensitive as the most sensitive animal species |
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What are the issues with bioassays?
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1. Extrapolation: animals to humans 2. Extrapolation: high dose to low dose 3. Cost relative to benefits 4. Animal use and welfare |
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What are the four standard bioassays done? |
1. Testing for acute effects (including death; LD50/LC50 determined) 2. Testing for Toxicity of Repeated Exposure (subacute; subchronic) - high dose that causes toxicity but not more than 10% fatalities, low dose with no toxic effects,a nd intermediate dose 3. Testing for Toxicity and Carcinogenicity of chronic exposure 4. Testing for Developmental and Reproductive Toxicity |
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What is a quantal response? |
An "all or none" response such as in tests for acute effects of toxicants -dead or not dead Quantal bioassay follow a Gaussian distribution curve: each step is the % of new responders compared to previous dose |
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How is the LD50 or LC50 found? |
Plot cumulative response and find the x-intercept at 50% response |
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What are the classes of toxicity?
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Class 1: Practically non-toxic (LD50 > 15k mg/kg)
Class 2: Slightly toxic (5k-15k mg/kg) Class 3: Moderately toxic (500-5k mg/kg) Class 4: Very toxic (50-500 mg/kg) Class 5: Extremely toxic (5-50 mg/kg) Class 6: Supertoxic (LD50 <5 mg/kg; less than 1 pinch lethal dose in humans) |
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How do we transform sigmoidal data into linear data?
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Y-axis is converted to 'probits' -closer to standard deviations than cumulative response -Values are converted using a chart Plot is probit vs log dose |
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What is the ED50, TD50, LD50, and TI? |
ED50 = Effective dose at which 50% of the population receives the effect we want TD50 = Toxic dose where bad things start happening in 50% of population LD50 = Lethal dose in 50% of the population TI = therapeutic index: TD50/ED50, high values mean that the drug is safe |
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What is the difference between potency and efficacy?
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Potency = the amount required to produce an effect of given intensity Efficacy = refers to maximum response achievable |
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What is the difference between hormesis and nonmonotonic dose-response curves? |
Hormesis: U-shaped curve where too little or too much is dangerous Nonmonotonic: Observed with endocrine disruptors (toxins that affect hormonal responses at very low levels) -response decreases at high levels, goes against one assumption of bioassays (dose extrapolation) |
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Why are subchronic bioassays used? |
1. To provide information on all types of subchronic toxicity
2. Establish dose regimens for chronic studies 3. Provide data which will allow an estimate to be made of the MTD (max tolerated dose) 4. Develop biomarkers: xenobiotically induced variation in cellular or biochemical components or processes, structures, or function that is measurable in a biological system or sample |
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What changes are seen from biomarkers? |
1. Enzyme activity and/or location 2. Changes in hormone levels 3. Increased/decreased expression of genes that respond to toxicants 4. Changes in histology of cells |
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What factors do we divide NOAEL by to get Acceptable Daily Intake?
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Divide by 10 for potential interspecies variation -Another 10 for intraspecies variation -Divide by another 10 if no NOAEL, only LOAEL -If in food, divide by another 10 to take infants and children into consideration |
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Why have only 10% of chemicals in commercial use been tested for toxicity? |
-Not required -Lack of funds, personnel, facilities -Expensive -Difficult to test interactions -Non pharmaceuticals are considered innocent until proven guilty |
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What are alternatives to bioassays? |
1. QSAR: Quantitative structure activity relationship -mathematical modeling of chemical structures, tries to predict toxicity based upon relationships in chemical structures 2. Cell culture based assays -cells cultured on petri plates and subjected to chemicals |
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What factors affect toxicity? |
Specific toxicant, concentration of toxicant, form of toxicant (e.g. mercury to methylmercury), interactions between toxicants (additive, synergistic, potentiation, antagonism), duration of exposure, species of organism, age or life stage of organism (strong on younger), genetics of organism (susceptibility and resistance factors)
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What is potentiation? |
When a non-toxic chemical makes a toxicant even more toxic |
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What is tolerance and resistance? |
Tolerance: When prior exposure of a toxicant alters the metabolism or physiology of the organism so that subsequent exposures to it result in a reduced toxic effect Resistance: genetically encoded ability for an organism to avoid a toxic response when exposed to a toxicant -Mechanisms: Selections for a polymorphism of a resistance factor gene currently in a population; selection for a new mutation in a resistance factor gene; new gene picked up from environment or other organism; multiple copies of a gene already in the organism arise |
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What is toxicogenomics? |
Deals with collection, interpretation, and storage of info about gene and protein activity within particular cell or tissue of an organism in response to toxic substances |
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What is toxicokinetics? |
How toxicants are absorbed, metabolized, distributed, and eliminated -Absorption: when toxicants cross cell membranes and enter bloodstream of lymph system. Toxicants mostly diffuse through tissues before entering the blodstream -hydrophobic toxicants easily diffuse (like through skin), larger toxicants use endocytosis |
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How do toxins travel through the digestive system? |
-chemicals absorbed in the gut, first go through the liver via hepatic portal -major site of toxin metabolism -target organ for many toxicants -Can extract toxins and excrete them into bile Transporters move xenobiotics from the intestine to the bloodstream |
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How are toxicants stored throughout the body?
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Blood: proteins such as albumin absorb toxicants, but this is reversible Liver and kidney: involved in metabolsim and exretion, but can also store toxicants Fat: most are hydrophobic, so will readily partition into adipose tissue |
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How are toxicants kept out of the brain? |
Tight junctions in capillaries MDR transporters in capillary endothelial cells that pump chemicals back into bloodstream |
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What is biotransformation? |
Where chemicals are changed in the body, such as adding multiple enzymes to a toxin to make it less lipophilic, less reactive, more water soluble and excretable |
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What happens in phase I metabolism of biotransformation? |
-Small molecular weight changes: hydroxylation, reduction, hydrolysis -adds or reveals a functional group -Commonly catalysed by cytochrome P450 P450 hydroxylates alphatic or aromatic carbons, epoxidates double bonds, dealkylates heteroatoms |
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What happens in Phase II reactions of biotransformation? |
Involves complexing or conjugation of toxicants with relatively large and highly water-soluble adducts to form glucuronides, sulfates, and glutathione adducts -4 primary enzyme activities: Glucuronic acid, sulfate, glutathione, and acetyl -Glutathione adducts are further metabolized in kidney to mercapturic acids of the toxicant, filter derivatives into urine |
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What is the difference in the types and degree of biotransformations between cats, fish, and gut microbes? |
Cats don't use glucuronic acid as a phase II conjugant -Fish in general don't biotransform toxicants to the same degree (pump out with gills) -Gut microbes can also biotransform toxicants |
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What is the difference between toxicokinetics and toxicodynamics, and their relation to the molecular target concept? |
Toxicokinetics is how toxicants are absorbed, metabolized, distributed and eliminated. Toxicodynamics is what happens after a molecular target is altered. |
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How do ROS's damage biomolecules? |
-Initiate destructive oxidative chain reactions of any biomolecule with double bonds: lipid peroxidation of membranes and DNA strand breaks occur e.g. hydrogen peroxide 1: ROS reacts with an unsaturated lipid to form lipid radical 2: LR combiend with O2, forms peroxyl radical and passes free electron onward to repeat 3: Peroxyl radical turned into lipid peroxide, forms nasty aldehydes |
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What enzymes detoxify ROS's and how? |
Superoxide dismutase, glutathione peroxidase, and catalase detoxicate superoxide anion radical Tocopherol can end chain reaction by donating an electron and remaining stable |
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What three biochemical disorders affect homeostasis and what happens to the cell when they occur? |
1. ATP depletion: any toxicant that interferes with glycolysis, ETC, ATP synthase, or oxygen delivery will decrease levels of ATP and cell can't carry out its normal functions 2. Sustained rise intracellular in Ca2+: If toxicant increases [Ca2+] - increased pumping of Ca2+ into mitochondria, depleting ATP and decreasing ATP synthesis. Disrupts actin cytoskeleton too, and hydrolytic enzymes are activated by Ca2+ 3. Overproduction of ROS and RNS: high Ca2+ in mitochondria activates tricarboxylic acid cycle, causing more electrons to flow through the ETC to ATP snythase. If ATP synthase is inhibited, ETC overhwlmed and ROS and RNS species formed. Lipid peroxidation occurs. |
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How do the three biochemical disorders affecting homeostasis work together to further increase cellular dysfunction? |
-Depletion of ATP reserves deprives Ca2+ pumps of fuel, elevating Ca2+ in cytoplasm -Cell compensates by pumping Ca2+ into mitochondria which decreases the H+ separation across the mitochondrial membrane and hinders ATP synthase -causes formation of ROS and RNS, oxidize and inactivate Ca2+ pumps, aggravating hypercalcemia -ROS and RNS drain ATP reserves as cell tries detoxifying them ROS and RNS directly damage membranes, cause leakage of ions out of the cell, even more Ca2+ enters cell |
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What is the difference between apoptosis and necrosis, and how does the cell decide which will occur? |
Necrosis: mitochondrial permeability transition occurs, where a pore opens in the mtch membrane and all contents leak into cytosol. Cell swells and bursts and plasma membrane becomes permeable Apoptosis: Programmed cell death, triggered by cytochrome C leaking from mitochondria -Cell decides based on number and extent of mitochondrial damage. Also if DNA is damaged. |
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What is the basic idea behind carcinogenesis? |
Cancer develops when enough genes mutate so that: 1. Genes/proteins that normally signal the cell to enter cell division are permanently on (oncogenes) 2. Genes/proteins that normally signal to not divide if DNA damage detected are turned off (tumor suppressor genes) 3. Genes/proteins signaling damaged cell to enter apoptosis are turned off (also tumor suppressor genes) |
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How can mutagens alter DNA? |
-Bind to DNA as adducts: cell repairs by an imperfect mechanism and a different nucleotide base accidentally can be used to fix the DNA strand -> mutation -Directly damage DNA backbone or bases. ROS do this but so will radiation. Error-prone repair can cause mutations |
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What two ways can a toxicant be a carcinogen but not a mutagen? |
1. Toxicants causing lots of cell death increase cell turnover = more chances for error in replication to occur 2. Hormone mimics that signal for a cell to divide when it shouldn't: more cell divisions = higher chance of mutation |
